DESCRIPTION (Applicant's Description) The broad, long term objective of the proposed research is to identify genes which, if mutated, are associated with predisposition to prostate cancer. This pilot study will focus specifically on mutations in the DNA polymerase Beta gene. The specific aims of the pilot study are first, to ascertain whether a mutation in the gene encoding DNA polymerase Beta is associated with genetic predisposition to prostate cancer and second, to determine if alterations found in the Pol Beta gene have the potential to cause prostate cancer. To accomplish our goals we will sequence every exon and splice junction of the polymerase Beta gene obtained from constitutional tissue of patients with familial prostate carcinoma and compare these sequences with those from unaffected individuals, with no family history of prostate cancer. To understand the mechanism of how mutations in the DNA polymerase Beta gene relate to prostate cancer we will perform functional assays with polymerase Beta mutant proteins. Within one year from the starting date of this proposal we will determine whether mutations in the DNA polymerase Beta gene are associated with predisposition to prostate cancer. Because polymerase Beta is a well-characterized protein, we will be able to determine the mechanism by which a polymerase Beta variant results in prostate cancer. Therefore, this pilot study has the potential to determine if mutations in DNA polymerase Beta predispose humans to prostate cancer and to identify mechanisms which underlie the development of this neoplastic disease.